Severe burn injury leads to a hypercatabolic state that lasts for up to one year and results in the dramatic loss of skeletal muscle mass. The accelerated protein loss contributes to what is likely the most rapid rate of muscle degradation and subsequent muscle atrophy observed. The loss of lean body mass increases the patient's risk for infection and impairs wound healing. While it is well accepted that prolonged skeletal muscle catabolism occurs due to burn injuries in humans, the molecular events underlying this have yet to be elucidated. Also unknown is why skeletal muscle atrophy persists even after the patient's burn wounds have "healed." To answer these questions, serum and muscle samples will be obtained from subjects burned over 20-60% of total body surface area and compared to those from matched controls. Burn samples will be obtained four to ten days post-burn injury and again six to nine months post-burn injury after injuries have healed. Muscle samples will be tested to determine the activation of molecular signaling pathways involved in muscle protein synthesis and degradation. Determination of which protein synthesis and degradation pathways are upregulated or suppressed during the recovery process is crucial to understanding how to minimize post-burn muscle loss. To isolate the effects of the burn milieu on skeletal muscle, an in vitro system will be used. Serum from burn subjects in the early and late stages of recovery will be applied to healthy, human skeletal muscle cells. Various markers of muscle growth and protein metabolism will be measured to determine the effect of burn-serum on healthy skeletal muscle. The results obtained from these in vitro experiments will determine how circulating factors such as inflammatory cytokines affect remote skeletal muscle catabolism. After completion of these studies, a better understanding of burn-induced muscle atrophy will exist. This research project holds an extremely high degree of scientific impact for scientists and doctors within the burn community as well as researchers interested in skeletal muscle atrophy. It must be emphasized that treatment efficacy will not be achieved without first having a better understanding of the underlying mechanisms leading to muscle protein losses in these patients. The research project described will provide important mechanistic data that are expected to markedly influence the approach to treating human muscle atrophy consequent to burn injury. PUBLIC HEALTH RELEVANCE: During recovery from severe burn injury, a dramatic loss of skeletal muscle occurs throughout the body. These studies will help us understand the molecular and cellular aspects that lead to this muscle loss. Understanding the mechanisms controlling muscle loss after burn will allow for the development of treatments to prevent it.